Next-Generation Sequencing Assays and Target Therapy Changing Outcomes in Childhood ALL

Over the past 60 years, the cure rate in childhood acute lymphoblastic leukemia (ALL) has gone from 0% to 90% thanks to stepwise improvements in chemotherapy. Now, a new review is suggesting that treatments developed over the past 10-15 years may quickly lead to a cure for childhood ALL who are not in remission presently. However, these improved outcomes may only be limited to countries that have next-generation sequencing assays and targeted treatment options at their disposal.  

Improvements in systemic combination chemotherapy and intrathecal chemotherapy have helped increase the survival rate of childhood ALL. The use of minimal residual disease (MRD) measurements early in therapy has significantly improved risk group stratification and better identify which patients may need treatment intensification and may be at  high-risk of relapse. MRD also has led to a reduction of treatment in low-risk patients.  

“The use of targeted immunotherapies has decreased toxicity and improved survival. Blinatumomab improves survival in relapsed ALL and is much less toxic than cytotoxic chemotherapy. CAR T-cells improved survival in relapsed and refractory ALL and allowed many children to avoid HSCT (hematopoietic stem cell transplantation),” said study co-author Stephen Hunger, MD, of the Division of Oncology, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia in Pennsylvania.

It has been theorized that the recent development of more sensitive MRD technologies may be able to further improve risk stratification and lead to more precision medicine. The authors note that molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. 

First author Rob Pieters, MD, with the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands, said we are now in a new era. “Especially because of the new immunotherapeutic modalities and the improved knowledge of molecular genetic abnormalities underlying ALL,” Dr Pieters explained.

The authors noted that the introduction of immunotherapies, including bispecific antibodies, antibody-drug conjugates (ADC), and cellular therapies, has changed treatment for refractory/relapsed (r/r) ALL and allogeneic stem cell transplantation in patients with relapsed and refractory ALL. 

Ching-Hon Pui, MD, chair of the St. Jude Department of Oncology, Memphis, Tennessee,  said a notable number of patients who previously had leukemia that was considered incurable, can now expect to survive the disease. “Building upon these achievements, we and others have initiated studies aimed at extending these therapeutic breakthroughs to newly diagnosed patients with higher-risk leukemia. Our objective is to replace the harsh and toxic conventional treatments with more precise, targeted medicines, with the goal of enhancing both their cure rates and quality of life,” said Dr Pui.

Although recent advances have been truly remarkable, persistent challenges remain. For example, Dr Pui noted roughly 5% of children with ALL carry inherited germline predisposition genes, putting them at a heightened risk of treatment-related toxicities and subsequent primary and secondary neoplasms. 

“We have seen improvements in leukemia relapse and survival due to the use of targeted molecular therapies in specific subtypes of childhood ALL. The most notable being the use of ABL Tyrosine Kinase inhibitors in Philadelphia Chromosome Positive ALL,” Dr Hunger said.  

Almost all children with high-risk ALL subtypes underwent allogeneic stem cell transplant 20 years ago, and overall, less than half of these children survived. “Today, survival is more than 70% with less than 20% undergoing HSCT in first remission,” Dr Hunger said.

The authors noted that genome-wide association studies have now identified multiple noncoding polymorphisms influencing the risk of developing ALL, commonly at loci encoding tumor suppressors or hematopoietic transcription factors (ARID5B, BAK1, CDKN2A/CDKN2B, BMI1-PIP4K2A, CEBPE, ELK3, ERG, GATA3, IGF2BP1, IKZF1 IKZF3, USP7, and LHPP).